Regulation of Ich-1 pre-mRNA alternative splicing and apoptosis by mammalian splicing factors

Jiang, Zhihong; Zhang, Wanjiang; Rao, Yi; Wu, Jane Y.

doi:10.1073/pnas.95.16.9155

Cited by 137 publications

(109 citation statements)

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“…In addition, overexpression of SC35 alters the splicing of caspase-2 mRNA, in favor of the pro-apoptotic isoform accumulation. 7 Furthermore, phosphorylation of SR proteins, which is known to control their sub-cellular localization as well as their activities, has been reported during apoptosis. However, the upstream signaling molecules that regulate the expression and/or activity of SR proteins during apoptosis, as well as the endogenous targets of SR proteins in this context remain largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Alternative splicing of casp-2 proceeds through selective insertion or removal of exon 9 giving rise to anti-apoptotic caspase-2S and proapoptotic caspase-2L isoforms respectively. 7 The use of a distant splice donor site at the 3 0 -end of exon 8 of human caspase-8 pre-mRNA leads to the synthesis of an alternative splice variant, caspase-8L, a competitive inhibitor of caspase-8. [15][16] The inclusion or exclusion of an exon cassette in caspase-9 causes the expression of two splice variants, namely the pro-apoptotic caspase-9a and antiapoptotic caspase-9b.…”

Section: Wild-type E2f1 -/-mentioning

confidence: 99%

“…5 Interestingly, changes in SR protein phosphorylation have been observed upon apoptotic stimulation following activation of the Fas receptor. 6 In addition, in vitro overexpression experiments have suggested a potential role for SR proteins in the control of the splicing of pre-mRNAs encoding apoptotic regulators [7][8] Moreover, depletion of the ASF/SF2 SR protein has been reported to induce apoptosis. [8][9] Nevertheless, whether individual SR proteins are necessary to modulate alternative splicing of mRNAs encoding apoptotic factors remains largely unknown, as well as the factors that control expression and/or activity of SR proteins in this context.…”

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E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35

et al. 2008

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The transcription factor E2F1 has a key function during S phase progression and apoptosis. It has been well-demonstrated that the apoptotic function of E2F1 involves its ability to transactivate pro-apoptotic target genes. Alternative splicing of pre-mRNAs also has an important function in the regulation of apoptosis. In this study, we identify the splicing factor SC35, a member of the SerRich Arg (SR) proteins family, as a new transcriptional target of E2F1. We demonstrate that E2F1 requires SC35 to switch the alternative splicing profile of various apoptotic genes such as c-flip, caspases-8 and -9 and Bcl-x, towards the expression of pro-apoptotic splice variants. Finally, we provide evidence that E2F1 upregulates SC35 in response to DNA-damaging agents and show that SC35 is required for apoptosis in response to these drugs. Taken together, these results demonstrate that E2F1 controls pre-mRNA processing events to induce apoptosis and identify the SC35 SR protein as a key direct E2F1-target in this setting. Cell Death and Differentiation (2008) 15, 1815-1823 doi:10.1038/cdd.2008 published online 19 September 2008 Pre-mRNA splicing is an essential step for the expression of most genes in higher eukaryotic cells. This process has emerged as an important mechanism of genetic diversity as about 74% of human genes undergo alternative splicing, leading to the production of various protein isoforms. 1 SC35 belongs to the serine/arginine-rich (SR) protein family, one of the most important class of splicing regulators. Members of the SR family have a modular structure consisting of one or two copies of an N-terminal RRM (RNA-recognition motif) followed by a C terminus rich in serine and arginine residues known as the RS domain. They act at multiple steps of spliceosome assembly and participate in both constitutive and alternative splicing. 2 Together with most of the other splicing factors, SR proteins localize to nuclear subregions termed nuclear speckles. 3 Extensive serine phosphorylation of the RS domain has an important function in the regulation of both the localization and the activities of SR proteins. 4 Although the splicing functions of SR proteins have been well documented in vitro, their roles and physiological targets in vivo are less well known. However, based on gene targeting experiments demonstrating that they are required for cell viability and/or animal development, SR proteins undoubtedly control essential biological functions.Apoptosis is one of the cellular processes in which alternative splicing has an important regulatory function. Indeed, a remarkable number of transcripts that encode proteins involved in the apoptotic pathway are subjected to alternative splicing. This usually drives the expression of proteins with opposite functions, either pro-or anti-apoptotic. 5 Interestingly, changes in SR protein phosphorylation have been observed upon apoptotic stimulation following activation of the Fas receptor. 6 In addition, in vitro overexpression experiments have suggested a potential role for ...

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Section: Discussionmentioning

confidence: 99%

Section: Wild-type E2f1 -/-mentioning

confidence: 99%

mentioning

confidence: 99%

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E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35

et al. 2008

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“…It was shown that phosphorylated SR proteins associate with the U1-snRNP complex and snoRNPs during apoptosis (Utz et al, 1998;Overzet et al, 2000), and our results show that PSF is another component of this complex during apoptosis. Another study suggests that splicing factors regulate apoptosis, perhaps by regulating caspase activity (Jiang et al, 1998). It is speculated (Prasad et al, 1999) that the phosphorylation of splicing factors at unique residues facilitates the inactivation of these proteins either by rendering them inactive or by irreversibly complexing them with other proteins of the splicing machinery and thus titrating them out of the splicing reaction.…”

Section: Discussionmentioning

confidence: 99%

Nuclear Relocalization of the Pre-mRNA Splicing Factor PSF during Apoptosis Involves Hyperphosphorylation, Masking of Antigenic Epitopes, and Changes in Protein Interactions

Shav‐Tal

Cohen

Lapter

et al. 2001

MBoC

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The spatial nuclear organization of regulatory proteins often reflects their functional state. PSF, a factor essential for pre-mRNA splicing, is visualized by the B92 mAb as discrete nuclear foci, which disappeared during apoptosis. Because this mode of cell death entails protein degradation, it was considered that PSF, which like other splicing factors is sensitive to proteolysis, might be degraded. Nonetheless, during the apoptotic process, PSF remained intact and was N-terminally hyperphosphorylated on serine and threonine residues. Retarded gel migration profiles suggested differential phosphorylation of the molecule in mitosis vs. apoptosis and under-phosphorylation during blockage of cells at G1/S. Experiments with the use of recombinant GFP-tagged PSF provided evidence that in the course of apoptosis the antigenic epitopes of PSF are masked and that PSF reorganizes into globular nuclear structures. In apoptotic cells, PSF dissociated from PTB and bound new partners, including the U1-70K and SR proteins and therefore may acquire new functions. INTRODUCTIONSplicing factors are found within the nucleus both in a diffuse form and in distinct domains termed interchromatin granules (IG) or "speckles" (Spector, 1993). These functional compartments are spatially dynamic with regard to movement and composition (Eils et al., 2000). Splicing factors within IGs are highly mobile and are constantly associating and dissociating from their compartments (Phair and Misteli, 2000). The mAb, B92, which recognizes the polypyrimidine tract binding protein (PTB)-associated splicing factor (PSF), produces typical specked nuclear pattern in immunostaining. These PSF speckles disappear during granulocytic differentiation (Lee et al., 1996;Shav-Tal et al., 2000). We recently showed that this disappearance is associated with partial degradation (Shav-Tal et al., 2000) and by the formation of alternative nuclear structures (Shav-Tal et al., 2001). The present study indicates that PSF speckles disappear also through a different mechanism, involving conformational changes that cause breakdown of PSF speckles and relocalization of the molecule in the nucleus. The functional nature of speckles is a matter of some controversy (for review, see Park and De Boni, 1999). These structures have been suggested to play a role in storage and recycling of splicing factors (Jimenez-Garcia and Spector, 1993), whereas a portion may act as reservoirs for the recruitment to active sites of transcription (Huang and Spector, 1996;Zeng et al., 1997). This view does not predict a direct involvement of speckles in pre-mRNA splicing. On the other hand, it has been shown that nascent mRNA transcripts and transcription sites are closely associated with speckles, that transcription occurs at the surface of speckles (Clemson and Lawrence, 1996), and that microinjected pre-mRNAs have high affinity to speckles (Wang et al., 1991). It has thus been proposed that speckles can act coordinately in transcription and splicing and that pre-mRNA splicing can take place bo...

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“…Thus, several apoptosis-related genes have been identified, for example, murine CD95L (Ayroldi et al, 1999), CD95 (Cascino et al, 1995), caspase-2, -8, -9 (Jiang et al, 1998;Srinivasula et al, 1999;Cote et al, 2001;Eckhart et al, 2001), cFLIP (Scaffidi et al, 1999) and survivin Conway et al, 2000;Krieg et al, 2002), which are alternatively Revised 4 November 2002; accepted 25 November 2003 processed and thereby may exert distinct regulatory functions in the fine tuning of apoptosis.…”

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confidence: 99%

TRAIL-β and TRAIL-γ: two novel splice variants of the human TNF-related apoptosis-inducing ligand (TRAIL) without apoptotic potential

Krieg

Wenzel

et al. 2003

Br J Cancer

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Tumour necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL/APO2L) is a recently identified member of the TNF family, which induces programmed cell death in a variety of neoplastic cell types, but not in most nonneoplastic cells. In this study, we report on the identification of two novel alternative splice variants of TRAIL in neoplastic and non-neoplastic human cells lacking either exon 3 (TRAIL-b) or exons 2 and 3 (TRAIL-g). In both splice variants, loss of exon 3 resulted in a frame shift generating a stop codon with consecutive extensive truncation in the extracellular domain. Ectopic expression revealed a loss of proapoptotic potential for both alternative splice variants. In contrast to the predominantly cytoplasmatic localisation of GFP-tagged TRAIL-a and TRAIL-b, TRAIL-g showed an additional association with the cell surface and nuclear membrane. In conclusion, alternative splicing might be involved in fine tuning of TRAIL-induced apoptosis and underlines the complexity of the TRAIL system.

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Regulation of Ich-1 pre-mRNA alternative splicing and apoptosis by mammalian splicing factors

Cited by 137 publications

References 20 publications

E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35

E2F1 controls alternative splicing pattern of genes involved in apoptosis through upregulation of the splicing factor SC35

Nuclear Relocalization of the Pre-mRNA Splicing Factor PSF during Apoptosis Involves Hyperphosphorylation, Masking of Antigenic Epitopes, and Changes in Protein Interactions

TRAIL-β and TRAIL-γ: two novel splice variants of the human TNF-related apoptosis-inducing ligand (TRAIL) without apoptotic potential

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